Our major goals are simple: we intend to determine a major fraction (see below) of the sequence of the genome of budding yeast (Saccharomyces cerevisiae). As an integral part of this effort, we intend to improve the speed and reduce the cost of production sequencing, largely through automation. We want to integrate development of new methods and their implementation in production so that new processes are continually tested and applied in such a way as to minimize the "down-time". Limited sequencing of human DNA will be done as well, in order to assess the generality of our evolving methods. We plan to apply novel methods of testing the accuracy of sequences obtained in production. We propose to explore new ways in which knowledge of sequence can be used, on a genome- wide basis, to get some idea of the biological functions of yeast genes. As we approach the end of the yeast genome, we propose to phase into production sequencing of carefully chosen megabase-scale segments from chromosome 4 of the human.